PROJECT SUMMARY/ABSTRACT Our goal is to identify genes that increase risk for affective and psychotic disorders like schizophrenia, bipolar disorder and major depression. Although these highly heritable diseases are associated with substantial morbidity and mortality, their etiologies remain poorly understood. Identifying genes that contribute to their risk should provide critical information leading to the development of novel diagnostic and therapeutic strategies. We propose an eight site international consortium designed to identify rare causal variants for affective and psychotic illnesses using extended multiplex pedigrees. These multigenerational families were previously identified and include at least three individuals with confirmed diagnoses. We focus on the identification of rare variants (with population MAF ? 0.01) that have a large absolute effect size, although it may be present in a small number of related affected individuals. While such rare functional variants may have a small effect on population attributable risk or variant-specific heritability, they can be sufficient to verify that a given gene is involved in illness risk. Pedigree-based studies represent an implicit enrichment strategy for identifying the rarest (e.g., private or pedigree-specific) variants, as Mendelian transmissions from parents to offspring maximize the chance that multiple copies of rare variants exist in the pedigree. Whole genome sequencing (WGS) allows a comprehensive search for rare single nucleotide variants (SNVs) or more complex sequence variation such as CNVs or INDELS. To identify rare, potentially private, variants that increase risk for affective or psychotic illness, we will create a repository of 4043 individuals from previously collected multiplex pedigrees (n=331) that will be analyzed with WGS. 1915 of these individuals have available WGS and we will obtain sequence data for 2128 additional subjects. Phenotypes include classical dichotomous diagnoses, quantitative scales derived from standardized interviews reflecting dimensional symptom classes, and neurocognitive endophenotypes. Our specific aims are to: 1) synergize phenotypic assessments, create dimensional indices of psychopathology, and rank endophenotypes across sites; 2) obtain WGS on 2128 individuals from extended pedigrees by direct sequencing of 1000 samples at 30x coverage and perform highly accurate pseudo-sequencing using a high density SNP framework to obtained the remaining 1128; 3) localize and identify QTLs influencing illness phenotypes /endophenotypes; 4) perform pedigree-based genome-wide association using likely functional variants; 5) identify rare functional CNV/INDELs influencing illness risk or endophenotypes; 6) perform gene-centric association tests in an independent sample. Our collaborative project includes applications from Yale University (DC Glahn, PD/PI), Texas Biomedical Research Institute (J Blangero, PD/PI) and the University of Pennsylvania (RE Gur, PD/PI). In addition, the Universities of Pittsburgh (V Nimgaonkar), Costa Rica (H Ravents), Edinburgh (AM McIntosh), and Western Australia (A Jablensky) and the intramural NIMH (F McMahon) will participate.